Atopic dermatitis (AD) is a chronic/relapsing inflammatory skin disease characterized by symptoms including intense pruritus (e.g., severe itch) and by scaly and dry eczematous lesions. Severe disease can be extremely disabling due to major psychological problems, significant sleep loss, and impaired quality of life, leading to high socioeconomic costs. The pathophysiology of AD is influenced by a complex interplay between Immunoglobulin E (IgE)-mediated sensitization, the immune system, and environmental factors. The primary skin defect may be an immunological disturbance that causes IgE-mediated sensitization, with epithelial-barrier dysfunction that is the consequence of both genetic mutations and local inflammation. AD often begins in childhood before age 5 and may persist into adulthood.
Typical treatments for AD include topical lotions and moisturizers, topical corticosteroid ointments, creams or injections. Most treatment options, however, offer only temporary, incomplete, symptom relief. Moreover, many patients with moderate-to-severe AD become resistant to treatment by topical corticosteroids or by calcineurin inhibitors. Thus, a need exists in the art for novel targeted therapies for the treatment and/or prevention of AD.
IL-17C is a secreted homodimer of the IL-17 protein family that was first cloned in 2000 (Li. et al. (2000). Proc. Natl. Acad. Sci. U.S.A. 97, 773-8). It was shown in vitro that IL-17C stimulates the release of TNF-α and IL-1β from the monocytic cell line THP-1 and induces the mRNA expression of inflammatory cytokines such as IL-1β, IL-6 and IL-23 in peritoneal exudate cells (PECs) and the 3T3 cell line (Yamaguchi et al. (2007) J. Immunol 179, 7128-36).
The role of IL-17C as a proinflammatory cytokine relevant for host defense was postulated in several studies (Chang et al. (2011) Immunity 35, 611-621, Song et al. (2011) Nature Immunology 12, 12, Ramirez-Carrozzi et al. (2011) Nature Immunology 12, 12). Also a potential role in the progression of specific tumours and cancerous tissues was recently shown (Song et al. (2014) Immunity 40, 140-152). Only recently, it was demonstrated that the IL-17RE/IL17-RA complex, preferentially expressed in epithelial cells, is the functional receptor for IL-17C and that epithelial cells are the predominant source of IL-17C.
In addition, antibodies that antagonize IL-17C were disclosed (e.g. in WO 1999/060127, WO 2013/057241) and it was demonstrated that antagonists of IL-17C are effective in the treatment of auto-inflammatory disorders, such as rheumatoid arthritis or psoriasis.